EA011155B1 - Phenylpyridinylpiperazin derivatives, the process to make them and the pharmaceutical composition containing them - Google Patents

Abstract

There proposed compounds of formula (I):wherein:X represents a C(O) or SOgroup,Rrepresents: a phenyl group,or an NRRgroup, wherein Rand R, which may be the same or different, each independently represent a hydrogen atom, a linear or branched (C-C)alkyl group, or a (C-C)cycloalkyl group,or Rand R, together with the nitrogen atom carrying them, form a 5- to 8-membered ring wherein one of the carbon atoms may be replaced by a nitrogen, oxygen or sulphur atom or by an SO or SOgroup, wherein the ring thereby defined is optionally bridged by a linear or branched (C-C)alkyl group and is optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C-C)alkyl group, (C-C)cycloalkyl group, hydroxy, oxo and an amino group (optionally substituted by one or more linear or branched (C-C)alkyl groups),Rrepresents a linear or branched (C-C)alkyl group or a (C-C)cycloalkyl group,their enantiomers and diastereoisomers, acid and base addition salts, and also a process to make them and pharmaceutical compositions containing compounds of formula (I).

Description

The present invention relates to novel phenylpyridylpiperazine compounds, to a process for their preparation, and to pharmaceutical compositions containing them.

The compounds of the present invention are especially valuable from a pharmacological point of view due to their specific interaction with central histamine receptors of type H ₃ and can be used in the treatment of neuropathologies associated with brain aging, mood disorders, eating behavior and the wake-sleep cycle, and hyperactivity syndrome with a lack of attention.

An aging population due to increased life expectancy from birth has brought with it a large increase in the number of age-related neuropathologies and especially Alzheimer's. The main clinical manifestations of brain aging and, in particular, age-related neuropathologies are memory deficits and cognitive functions that can lead to dementia.

Recent neuropharmacological studies have shown that in the central nervous system, histamine, through the central histaminergic systems, plays the role of a neurotransmitter or neuromodulator in physiological or physiopathological situations (Appi. Keu. No. Oxox 1986, 9, 209254; Pb.u8yu. 1. Neu., 1991, 71 , 1-51). Thus, histamine has been shown to be involved in various physiological and behavioral processes, such as thermoregulation, neuroendocrine regulation, circadian rhythm, cataleptic states, motility, aggressiveness, eating behavior, learning and memorization, and synoptic plasticity (Nakk et al., YkGashshegdyu peigopek.shogryo1ogu apb ΓυηοΙίοη, Vosa Ka1op, R.B. SKS Rgekk, 1991, pp. 196-208; Year no. gigoyoogu, 2001, 63, 637-672).

Of the 3 subtypes of histamine receptor (H _v H ₂ and H ₃₎ at the beginning, it was shown that the type H ₃ receptor is a presynaptic autoreceptor that controls the release of histamine (Thorn, 1987, 327, 117-123). Its activation inhibits the release and synthesis of histamine via the negative feedback mechanism (No. oxoxepse, 1987, 23, 149-157). The existence of presynaptic heteroreceptors capable of modulating the release of certain neuropeptides and many neurotransmitters, such as norepinephrine, serotonin, dopamine, CABA, acetylcholine and glutamate, was subsequently demonstrated (ΤίΡδ, 1998, 19, 177-183). Animal studies have shown that increasing endogenous extrasynaptic histamine levels by blocking receptors of the H3 type with the help of H3 antagonists makes it possible to promote wakefulness, learning and memory processes, regulate food intake, and combat convulsive attacks (Yearly. # 1,. 2000, 63, 637-672; No. igoks 1. Vyueyau. Neu., 2000, 24, 107-113). As a result, potential therapeutic indications for H ₃ antagonists are the treatment of cognitive deficits associated with brain aging and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Pick's disease, Korsakov’s disease and frontal or subcortical dementia of vascular or other origin, and treatment mood disorders, convulsions, hyperactivity disorder with a lack of attention, obesity, pain and narcoleptic conditions.

The compounds of the present invention, in addition to having a new structure, have pharmacological properties that are completely unexpected and valuable in this field.

More specifically, the present invention relates to compounds of formula (I)

in which X represents a C (O) or 8O ₂ group;

Κι represents a phenyl group or a group ΝΚ ₃ Κ ₄ in which H ₃ and H ₄ , which may be the same or different, each represent a hydrogen atom or a linear or branched (C1-C6) alkyl group or (C3-C8) a cycloalkyl group, or Κ3 and Κ4 together with the nitrogen atom carrying them form a 5- or 6-membered ring in which one of the carbon atoms can be replaced by a nitrogen, oxygen or sulfur atom or by an 8O or 8O ₂ group, the ring described by such thus, is optionally bridged by linear or branched ( A C ₁ -C ₆ ) alkyl group and / or is optionally substituted with one or two identical or different groups selected from a halogen, linear or branched (C1-C ₆ ) alkyl group, (C ₃ -C ₈ ) cycloalkyl group, hydroxy , oxo and amino groups (optionally substituted by one or more linear or branched _(C1-C6) alkyl groups);

K ₂ represents a linear or branched _(C1-C6) alkyl or (C ₃ -C ₈₎ cycloalkyl group, their enantiomers and diastereoisomers, and also their addition salts with a pharmaceutically acceptable acid or base.

Of the pharmaceutically acceptable acids, it may be noted without implying any limitation.

- 1 011155 reactions, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic, acid, ascorbic acid, methanesulfonic acid, camphoric acid, etc.

Among the pharmaceutically acceptable bases, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc., may be noted without implying any restrictions.

Preferred compounds in accordance with the invention are compounds of formula (I) in which Κι represents a ΝΚ3Κ4 group.

This invention more particularly relates to compounds of formula (I) in which K ₃ and K _4, together with the nitrogen atom carrying them, form a 5-8 membered ring in which one of the carbon atoms can be replaced by a nitrogen atom, oxygen or sulfur to either an 80 or 8O ₂ group, the ring thus described is not necessarily bridged by an alkyl chain and is unsubstituted or substituted, preferably by one or more halogen atoms, for example fluorine, or an alkyl group, for example a methyl group.

Even more preferably, preferred Κι groups are morpholinyl, thiomorpholinyl, piperidyl, piperazinyl, 4- (alkyl) piperazinyl, pyrrolidinyl, 2- (alkyl) -2,5 diazabicyclo [2.2.1] heptanyl, 2-oxa-5-azabicyclo [ 2.2.1] heptanyl.

X mainly represents 8O ₂ group.

A preferred K ₂ group is a cycloalkyl or (C ₂ -C ₆ ) alkyl group, more preferably an ethyl, isopropyl or cyclopentyl group.

Even more particularly, this invention relates to compounds of formula (I), which are

4 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) morpholine dihydrochloride, 1-isopropyl-4- {5- [4- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride, 1-cyclopentyl-4- {5- [4- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride, 1-cyclopropyl-4- {5- [4- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride,

1-ethyl-4- {5- [4- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride, 1-cyclobutyl-4- {5- [4- (piperidin-1-ylsulfonyl) phenyl ] pyridin-2-yl} piperazine dihydrochloride, 1- (5- {4 - [(4,4-difluoropiperidin-1-yl) sulfonyl] phenyl} pyridin-2-yl) -4-isopropyl piperazine dihydrochloride,

4 - ({4- [6- (4-cyclopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) morpholine dihydrochloride,

1-isopropyl-4- (5- {4 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} pyridin-2-yl) piperazine trihydrochloride,

4 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) thiomorpholine dihydrochloride,

1-cyclopentyl-4- {5- [4- (phenylsulfonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride,

1-cyclopentyl-4- {5- [3- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride, 1-isopropyl-4- {5- [4- (pyrrolidin-1-ylsulfonyl) phenyl ] pyridin-2-yl} piperazine dihydrochloride, 4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] - ^ dimethylbenzenesulfonamide dihydrochloride, No. cyclopentyl-4- [6- (4-isopropyl-1 piperazinyl) -3-pyridinyl] benzenesulfonamide,

1-cyclopentyl-4- {5- [4- (piperidin-1-ylcarbonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride, 1-isopropyl-4- {5- [4- (piperidin-1-ylcarbonyl) phenyl ] pyridin-2-yl} piperazine dihydrochloride, 1-methyl-4- {5- [4- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride, No. cyclopropyl-4- [6- (4 -isopropylpiperazin-1-yl) pyridin-3-yl] benzenesulfonamide dihydrochloride, No. (tert-butyl) -4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] benzenesulfonamide dihydrochloride,

4 - ({4- [6- (4-isobutylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) morpholine dihydrochloride, 1-isopropyl-4 - ({4- [6- (4-isopropylpiperazin-1 -yl) pyridin-3-yl] phenyl} sulfonyl) piperazine trihydrochloride,

4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] benzenesulfonamide dihydrochloride, 4 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl ) thiomorpholine 1,1-dioxide dihydrochloride,

1-ethyl-4 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) piperazine trihydrochloride,

4 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) thiomorpholine 1-oxide dihydrochloride,

1- {5- [4- (aziridin-1-ylsulfonyl) phenyl] pyridin-2-yl} -4-isopropylpiperazine dihydrochloride, 1-isopropyl-4- (5- {4 - [(2-methylpyrrolidin-1-yl ) sulfonyl] phenyl} pyridin-2-yl) piperazine dihydride

- 2 011155 rochloride,

1-isopropyl-4- {5- [4- (piperazin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine trihydrochloride, 1-cyclohexyl-4 - ({4- [6- (4-isopropylpiperazin-1 - il) pyridin-3-yl] phenyl} sulfonyl) piperazine dihydrochloride,

1 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) piperidin-4-one dihydrochloride,

1-isopropyl-4- (5- {4 - [(2-methylpyrrolidin-1-yl) sulfonyl] phenyl} pyridin-2-yl) piperazine dihydrochloride, enantiomer 1,

1- isopropyl-4- (5- {4 - [(2-methylpyrrolidin-1-yl) sulfonyl] phenyl} pyridin-2-yl) piperazine dihydrochloride, enantiomer 2,

2- ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptane,

1 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} • sulfonyl) -Y, M-dimethylpiperidin-4amine trihydrochloride,

1-cyclopentyl-4- (5- {4 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} pyridin-2-yl) piperazine trihydrochloride,

1 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) piperidin-4-ol dihydrochloride,

1-isopropyl-4- (5- {3 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} pyridin-2-yl) piperazine trihydrochloride,

1- (5- {4 - [(4-fluoropiperidin-1-yl) sulfonyl] phenyl} pyridin-2-yl) -4-isopropylpiperazine dihydrochloride,

4- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] benzoyl} morpholine dihydrochloride, 1-isopropyl-4- (5- {4 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} pyridin-2-yl) piperazine trihydrochloride,

1 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) -Y-methylpiperidin-4-amine trihydrochloride, (18,48) -5 - ({4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) -2-oxa-5azabicyclo [2.2.1] heptane dihydrochloride,

1 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) piperidin-4-amine trihydrochloride.

The present invention also relates to a process for preparing compounds of formula (I), wherein the process is characterized in that a compound of formula (II) is used as a starting material.

in which Κι and X take the values indicated for formula (I), and K and K ', which may be the same or different, each represent a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group or together form a linear or branched (C ₁ -C ₆ ) alkylene chain which is condensed in the presence of palladium (0) with a compound of formula (III)

in which K ₂ takes the values indicated for formula (I) and H1 represents a halogen atom, to obtain a compound of formula (I), where the compound of formula (I) is purified, if necessary, in accordance with conventional cleaning methods, separated, if appropriate , into its isomers, in accordance with conventional separation methods, and are converted, if desired, into its addition salt with a pharmaceutically acceptable acid or base.

The compounds of formulas (II) and (III), as shown above, are either commercially available or are prepared using conventional organic chemistry reactions.

Due to their pharmacological properties as histamine H ₃ receptor ligands, the compounds of the present invention are useful for treating cognitive impairment associated with brain aging and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Peak's disease, Korsakov’s disease and frontal or subcortical vascular dementia or of other origin, as well as for the treatment of mood disorders, convulsive episodes, attention deficit hyperactivity disorder, is fat, pain and narcoleptic states.

The present invention also relates to pharmaceutical compositions which comprise, as an active ingredient, at least one compound of formula (I), an isomer thereof or a salt thereof

- 3 011155 accession with a pharmaceutically acceptable acid or base, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.

Among the pharmaceutical compositions according to the invention, those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal or transdermal, intravaginal, rectal, nasal, sublingual, ocular or respiratory use can be especially noted.

The pharmaceutical compositions of the invention for parenteral injection especially include aqueous and non-aqueous sterile solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution to injection solutions or dispersions.

The pharmaceutical compositions of the invention for solid oral use in particular include tablets or dragees, sublingual tablets, sachets, capsules and granules, and for liquid oral, nasal, buccal or ophthalmic use in particular include emulsions, solutions, suspensions, drops, syrups and aerosols.

Pharmaceutical compositions for rectal or vaginal administration are preferably suppositories, and compositions for transdermal or transdermal administration especially include powders, aerosols, creams, ointments, gels and plasters.

The above pharmaceutical compositions illustrate the invention, but in no way limit it.

Among the inert, non-toxic, pharmaceutically acceptable excipients or carriers, it may be noted, without implying any restrictions, diluents, solvents, preservatives, wetting agents, emulsifiers, dispersants, binders, swelling agents, disintegrating agents, retarders, lubricants, absorbing agents, suspension agents, colorants, flavorings, etc.

The useful dosage varies according to the age and weight of the patient, by the use of the pharmaceutical composition used, the nature and severity of the disorder, and the use of any related treatments. Dosage ranges from 10 mg to 1 g per day in one or more applications.

The following preparations and examples illustrate the invention, but in no way limit it. The starting materials used are known products or products obtained according to known methods. The structures of the compounds described in the examples were determined according to conventional spectrophotometric methods (infrared spectrometry, nuclear magnetic resonance (NMR), mass spectrometry, etc.).

Preparation 1. 1- (5-Bromopyridin-2-yl) -4-isopropylpiperazine.

A solution containing 12.1 g of 2,5-dibromopyridine (51.1 mmol), 8.8 ml of 1-isopropylpiperazine (61.5 mmol) and 9.2 ml of ΌΒυ (61.5 mmol) was stirred overnight at 100 ° C. The temperature of the reaction mixture was brought to room temperature and the solution was diluted with water and extracted with ethyl acetate. The organic phases are collected, washed with brine, dried (MD80 ₄ ) and evaporated under reduced pressure. The precipitate was chromatographed on a 8ί0 ₂ column, eluting with a mixture of CH ₂ Cl ₂ / Me0H 98/2 and then 96/4 to give the title product.

Melting point: 76-78 ° C.

Elemental microanalysis:

FROM N N Vg % theory 50.72 6.38 14.79 28.12 % experiment 50.96 6.47 14.53 28.33

Preparation 2. 1- (5-Bromopyridin-2-yl) -4-cyclopentylpiperazine.

The procedure is the same as in Preparation 1, but 1-isopropylpiperazine is replaced with 1 cyclopentylpiperazine.

Melting point: 127-128 ° C.

Preparation 3. 1- (5-Bromopyridin-2-yl) -4-cyclopropylpiperazine.

The procedure is the same as in Preparation 1, but 1-isopropyl piperazine is replaced by 1 cyclopropyl piperazine.

Melting point: 110-115 ° C.

Preparation 4. 1- (5-Bromopyridin-2-yl) -4-ethylpiperazine.

The procedure is the same as in Preparation 1, but 1-isopropylpiperazine is replaced with 1-ethylpiperazine.

Melting point: 66 ° C.

Elemental microanalysis:

FROM N N % theory 48.90 5.97 15,55 % experiment 48.98 6.19 15.07

- 4 011155

Preparation 5. 1- (5-Bromopyridin-2-yl) -4-cyclobutylpiperazine.

The procedure is the same as in Preparation 1, but 1-isopropylpiperazine is substituted for cyclobutylpiperazine.

Melting point: 98-102 ° C.

Preparation 6. 1- (5-Bromo-2-pyridinyl) -4-methylpiperazine.

The procedure is the same as in Preparation 1, but 1-isopropylpiperazine is substituted for methylpiperazine.

Melting point: 71-73 ° C.

Preparation 7. 1- (5-Bromo-2-pyridinyl) -4-isobutylpiperazine.

The procedure is the same as in Preparation 1, but 1-isopropylpiperazine is substituted for isobutylpiperazine.

Melting point: 80 ° C.

Elemental microanalysis:

on 1 on 4 on 1-

FROM N N Vg % theory 52.36 6.76 14.09 26.79 % experiment 52.28 6.87 13.63 26.41

Example 1. 4 - ({4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) morpholine dihydrochloride.

Stage A. 4 - [(4-Iodophenyl) sulfonyl] morpholine.

To a solution of 50 g of 4-iodobenzenesulfonyl chloride (0.165 mol) in 500 ml of CH ₂ Cl ₂ , 46 ml of triethylamine (0.33 mol) are added and then, dropwise, 17 ml of morpholine (0.198 mol). Since the reaction is exothermic, the flask is placed in an ice bath until its temperature returns to room temperature. The reaction mixture was stirred for 1 h at room temperature. After washing the reaction mixture with approximately 100 ml of 1Ν HCl and then with 100 ml of water, the organic phase is dried (MgO ₄ ) and evaporated under reduced pressure. The solid precipitate thus obtained is resuspended in a small amount of isopropyl ether to obtain the title product after filtration and drying in vacuo.

Melting point: 141-144 ° C.

Stage B. [4- (Morpholin-4-ylsulfonyl) phenyl] boric acid.

To a solution of 25 g of the compound obtained in Step A (70.8 mmol) and 26 ml of triisopropyl borate in 400 ml of THF, cooled to -60 ° C, was added dropwise over 45 min and with a weak nitrogen stream 53 ml 1 6M solution of CuB (84.9 mmol) in hexane. After this, the reaction solution was stirred for 1 h 30 min at -60 ° C and then brought to room temperature for 2 h. The reaction mixture was treated with approximately 100 ml of 1Ν HCl and extracted 3 times with ethyl acetate. The organic phases are collected, washed with brine, dried (MgO ₄ ) and evaporated under reduced pressure. The resulting precipitate is chromatographed on a 81O ₂ column, eluting with CH ₂ Cl ₂ and then with a mixture of CH ₂ Cl ₂ / MeOH 98/2 and thereafter 95/5. After evaporation of the fractions, the residue was triturated in ethyl ether to give the title product after filtration.

Melting point: 104-110 ° C.

Step C. 4 - ({4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) morpholine dihydrochloride.

10.88 g of the compound obtained in Preparation 1 (38.3 mmol), 13.5 g of the compound obtained in Step B (49.8 mmol), 250 ml of dioxane and 190 ml of 0.4M No.-C.S. Oz in water is introduced into a three-necked flask. The reaction mixture is degassed by sparging with a stream of nitrogen for 30 minutes. Ρά (0) tetrakistriphenylphosphine (2.21 g, 1.91 mmol) was added and the reaction mixture was stirred at 100 ° C under a gentle stream of nitrogen for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl ether. . During the extraction, a precipitate forms, which is filtered off, washed with water and a small amount of ethyl acetate to obtain, after drying in vacuum, the first portion of the title product in the form of a base. The extracted phases are combined with the filtrate and the organic phase is separated and then washed with brine. The organic phase was dried (MgO ₄ ) and evaporated under reduced pressure. The precipitate obtained by evaporation is resuspended in ethanol and filtered off to obtain, after drying in vacuo, a second portion of the title compound in the form of a base. These 2 servings are combined and suspended in ethanol. Ethereal HC1 was added and the suspension was filtered to give the title product.

Melting point: 254-256 ° C.

Elemental microanalysis:

C H%, theory 52.48 6.41%, experiment 52.62 6.40

N 8 FROM! 11.13 6.37 14.08 10.93 6.50 14.45

Example 2. 1-Isopropyl-4- {5- [4- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine dihydride

- 5 011155 rochloride.

Stage A. 1 - [(4-Iodophenyl) sulfonyl] piperidine.

The procedure is the same as in stage A of example 1, but the morpholine is replaced with piperidine. Elemental microanalysis:

С Η N 8I%, theory 37.62 4.02 3.99 9.1336.13%, experiment 37.91 4.08 4.01 8.9836.54

Stage B. [4- (Piperidin-1-ylsulfonyl) phenyl] boric acid.

The procedure is the same as in stage B of example 1, but start with the product obtained in stage A. Melting point: 110 ° C.

Step C. 1-Isopropyl-4- {5- [4- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride.

The procedure is the same as in stage C of example 1, but start with the product obtained in stage B. Melting point: 249-252 ° C.

Elemental microanalysis:

C n N

C1%, theory 55.08 6.83%, experiment 54.83 7.00

11.17 6.39

11.05 6.18

14.14

13.74

Example 3. 1-Cyclopentyl-4- {5- [4- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine di hydrochloride.

The procedure is the same as in stage C of example 2, but the product of obtaining 1 is replaced by the product obtained in obtaining 2.

Melting point: 241-243 ° C.

Elemental microanalysis:

С Η N 8 С1%, theory 56.92 6.88 10.62 6.08 13.44%, experiment 56.65 7.11 10.37 6.13 13.07

Example 4. 1-Cyclopropyl-4- {5- [4- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine di hydrochloride.

The product of stage B of example 2 is reacted with the compound obtained in obtaining 3 under the conditions described in stage C of example 1.

Melting point: 204-208 ° C.

Elemental microanalysis:

C Η N 8 C1%, theory 55.31 6.46 11.22 6.42 14.20%, experiment 56.01 6.74 11.14 5.81 13.99

Example 5. 1-Ethyl-4- {5- [4- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride.

The product obtained in stage B of example 2 is reacted with the compound obtained in obtaining 4 under the conditions described in stage C of example 1.

Melting point: 245-247 ° C.

Elemental microanalysis:

C Ή%, theory 54.20 6.62%, experiment 54.87 7.01

N 8 C1 11.49 6.58 14.54 11.56 6.12 14.92

Example 6. 1-Cyclobutyl-4- {5- [4- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine di hydrochloride.

The product obtained in stage B of example 2, is reacted with the compound obtained in obtaining 5, under the conditions described in stage C of example 1.

Melting point: 250-253 ° C.

Elemental microanalysis:

C%, theory 57.77 6.79%, experiment 57.54 6.84

11.23 6.43

11.00 6.04

C1

13.81

11.69

Example 7. 1- (5- {4 - [(4,4-Difluoropiperidin-1-yl) sulfonyl] phenyl} pyridin-2-yl) -4-isopropyl piperazine dihydrochloride.

Stage A. 4,4-Difluoro-1 - [(4-iodophenyl) sulfonyl] piperidine.

- 6 011155

The procedure is the same as in stage A of example 1, but the morpholine is replaced with 4,4-difluoropiperidine. Melting point: 148-150 ° C.

Elemental microanalysis:

C H%, theory 34.12 3.12%, experiment 34.62 3.27

N 8I

3.62 8.2832.78

3.66 8.3033.36

Stage B. {4 - [(4,4-Difluoropiperidin-1-yl) sulfonyl] phenyl} boric acid.

The procedure is the same as in stage B of example 1, but start with the product obtained in stage A. Melting point: 289 ° C.

Step C. 1- (5- {4 - [(4,4-Difluoropiperidin-1-yl) sulfonyl] phenyl} pyridin-2-yl) -4-isopropyl piperazine dihydrochloride.

The procedure is the same as in stage C of example 1, but using the product obtained in stage B. Melting point: 260-262 ° C.

Elemental microanalysis:

from N N 8 C1 % theory 51,4 6.00 10.42 5.97 13.19 % experiment 51.07 5.85 10.03 6.07 13.84

Example 8. 4 - ({4- [6- (4-Cyclopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) morpholine di hydrochloride.

The Product of Step In Example 1, is reacted with the compound obtained in Preparation 3 under the conditions described in Step C of Example 1.

Melting point: 220 ° C.

Elemental microanalysis:

C%, theory 52.69 6.03%, experiment 52.67 6.04

C1

11.17 6.39

10.83 6.35

14.14

14.22

Example 9. 1-Isopropyl-4- (5- {4 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} pyridin-2-yl) piperazine trihydrochloride.

Stage A. 1 - [(4-Iodophenyl) sulfonyl] -4-methylpiperazine.

The procedure is the same as in stage A of example 1, but the morpholine is replaced with 4-methylpiperazine. Melting point: 181-182 ° C.

Step B. 1-Methyl-4- {[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] sulfonyl} piperazine.

5.4 g of the compound obtained in Step A (14.75 mmol), 4.52 g of bis- (pinacolato) diborane (19.18 mmol), 4.34 g of potassium acetate (44.25 mmol) and 50 ml of dimethylformamide injected into a 100 ml two-necked flask. The reaction mixture was degassed by sparging with a stream of nitrogen for 30 minutes, and then 165 mg of palladium acetate (0.737 mmol) was added. The reaction mixture was stirred under a weak stream of nitrogen for 2 hours and 30 minutes at 85 ° C. After cooling to room temperature, the reaction mixture was diluted with water and extracted with CH ₂ Cl ₂ . The organic phases are collected, washed with brine, dried and evaporated under reduced pressure. The resulting precipitate was chromatographed on δίθ ₂ (CH ₂ Cl ₂ / MeOH 95/5) to give the title product in the form of a creamy white solid.

Melting point: 126-136 ° C.

Step C. 1-Isopropyl-4- (5- {4 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} pyridin-2-yl) piperazine trihydrochloride.

The procedure is the same as in step C of example 1, but begins with the product obtained in step B above.

Melting point: 254-258 ° C.

Elemental microanalysis:

C H%, theory 49.96 6.56%, experiment 50.57 6.55

N 8 C1 12.66 5.80 19.23 12.50 5.82 18.50

Example 10.4 - ({4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) thiomorpholine dihydrochloride.

Stage A. 4 - [(4-Iodophenyl) sulfonyl] thiomorpholine.

The procedure is the same as in stage A of example 1, but the morpholine is replaced with thiomorpholine.

Melting point: 131 ° C.

Stage B. [4- (Thiomorpholin-4-ylsulfonyl) phenyl] boric acid.

The procedure is the same as in stage B of example 1, but start with the product obtained in stage A.

- 7 011155

Melting point:> 300 ° C.

Step C. 4 - ({4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) thiomorpholine dihydrochloride.

The procedure is the same as in stage C of example 1, but start with the product obtained in stage B.

Melting point: 248-253 ° C.

Elemental microanalysis:

FROM N N 8 C1 % theory 50.86 6.21 10.78 12.34 13.65 % experiment 51.51 6.41 10.35 11.74 13.95

Example 11. 1-Cyclopentyl-4- {5- [4- (phenylsulfonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride.

Stage A. 1-Bromo-4- (phenylsulfonyl) benzene.

To a solution of 199 μl of bromobenzene (1.88 mmol) and 361 μl of benzenesulfonyl chloride (2.83 mmol) in 4 ml of trifluoroacetic acid, 83 mg of indium chloride (0.376 mmol) are added in a row and then, dropwise, 25 μl of trifluoromethanesulfonic acid. The reaction mixture was stirred for 2 hours at 70 ° C and then brought to room temperature and diluted with ice water. After alkalizing to pH 10 by adding concentrated sodium hydroxide solution, the reaction mixture was extracted with CH ₂ Cl ₂ . The organic phases are collected, washed with saturated NaCl, dried (Mg ₄ O ₄ ) and evaporated under reduced pressure to give the title product in the form of a white solid.

Melting point: 95-99 ° C.

Elemental microanalysis:

FROM N 8 Vg % theory 48.50 3.05 10.79 26.89 % experiment 48.21 3.21 11.17 27.32

Stage B. [4- (Phenylsulfonyl) phenyl] boric acid.

The procedure is the same as in stage B of example 1, but start with the product obtained in stage A. Melting point: 287-290 ° C.

Step C. 1-Cyclopentyl-4- {5- [4- (phenylsulfonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride.

The procedure is the same as in stage C of example 1, but start with the product obtained in stage B, and replace the product of getting 1 to the product of getting 2.

Melting point: 155-159 ° C.

Elemental microanalysis:

C H%, theory 59.99 6.00%, experiment 60.36 5.86

N 8 C1 8.07 6.16 13.62 7.95 5.99 13,99

Example 12. 1-Cyclopentyl-4- {5- [3- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine di hydrochloride.

Stage A. 1 - [(3-Bromophenyl) sulfonyl] piperidine.

The procedure is the same as in step A of example 1, but begins with 3-bromobenzenesulfonyl chloride and piperidine.

Melting point: 87 ° C.

Elemental microanalysis:

C%, theory 43.43 4.64%, experiment 43.71 4.75

Vg

4.60 10.54 26.27

4.72 11.02 26.37

Stage B. [3- (Piperidin-1-ylsulfonyl) phenyl] boric acid.

The procedure is the same as in stage B of example 1, but start with the product obtained in stage A. Melting point: 115-119 ° C.

Step C. 1-Cyclopentyl-4- {5- [3- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine di hydrochloride.

The procedure is the same as in Step C of Example 1, but begins with the product obtained in Step B and the compound of Preparation 1 is replaced with the compound obtained in Preparation 2.

Melting point: 229-231 ° C.

Elemental microanalysis:

FROM N N 8 but % theory 56.92 6.88 10.62 6.08 13.44 % experiment 56.76 6.92 10.42 5.91 13.47

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Example 13. 1-Isopropyl-4- {5- [4- (pyrrolidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride.

Stage A. 1 - [(4-Iodophenyl) sulfonyl] pyrrolidine.

The procedure is the same as in stage A of example 1, but morpholine is replaced with pyrrolidine.

Melting point: 126 ° C.

Elemental microanalysis:

FROM n N 8 I % theory 35.62 3,59 4.15 9.51 37.64 % experiment 37.13 3.80 4.19 9.29 36.89

Stage B. [4- (Pyrrolidin-1-ylsulfonyl) phenyl] boric acid.

The procedure is the same as in stage B of example 1, but start with the product obtained in stage A. Melting point: 306 ° C.

Step C. 1-Isopropyl-4- {5- [4- (pyrrolidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride.

Example 14. 4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] -M, Y-dimethylbenzenesulfonamide di hydrochloride.

The procedure is the same as in stage C of example 1, but start with the product obtained in stage B. Melting point: 240 ° C.

Elemental microanalysis:

FROM N N 8 C1 % theory 54,20 6.62 11.49 6.58 14.54 % experiment 54.32 6.54 11.18 6.57 15.23

Stage A. 4-Iodine-No. Dimethylbenzenesulfonamide.

The procedure is the same as in stage A of example 1, but the morpholine is replaced with dimethylamine. Melting point: 128 ° C.

Elemental microanalysis:

C Η N 8 I%, theory 30.88%, experiment 31.56

3.24

3.32

4,50

4.41

10.31 40.79

10.10 39.50

Stage B. {4 - [(Dimethylamino) sulfonyl] phenyl} boric acid.

The procedure is the same as in stage B of example 1, but start with the product obtained in stage A. Melting point: 306 ° C.

Step C. 4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] -M, M-dimethylbenzenesulfonamide di hydrochloride.

The procedure is the same as in step C of example 1, but begins with the compound obtained in step B.

Melting point: 240 ° C.

Elemental microanalysis:

FROM N N 8 FROM! % theory 52.06 6.55 12.14 6.95 15,52 % experiment 52.39 6.68 11.69 6.91 15.74

Example 15. Y-cyclopentyl-4- [6- (4-isopropyl-1-piperazinyl) -3-pyridinyl] benzene sulfonamide dihydrochloride.

Stage A. Y-Cyclopentyl-4-iodobenzenesulfonamide.

The procedure is the same as in stage A of example 1, but the morpholine is replaced by cyclopentylamine. Stage B. Y-Cyclopentyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzenesulfonamide.

The procedure is the same as in step B of example 9, but begins with the product obtained in step A. Step C. Y-Cyclopentyl-4- [6- (4-isopropyl-1-piperazinyl) -3-pyridinyl] benzenesulfonamide dihydrochloride .

The procedure is the same as in step C of example 1, but begins with the compound obtained in step B.

Example 16. 1-Cyclopentyl-4- {5- [4- (piperidin-1-ylcarbonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride.

Stage A. 1- (4-Iodobenzoyl) piperidine.

To a suspension of 4.0 g of 4-iodobenzoic acid (16.13 mmol) in 40 ml of CH ₂ Cl ₂ , 3.65 ml of diisopropylethylamine (20.97 mmol) was added and then, after 10 minutes, 5.18 g of TBTi (16, 13 mmol). After stirring for another 10 minutes, 1.60 ml of piperidine (16.13 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture is washed 3 times with water and then one

- 9 011155 times saturated No. 1C1. After drying (Mg ₄ 0) and evaporation under reduced pressure, the precipitate is chromatographed on silica (CH ₂ Cl ₂ / acetone 9/1) to give the title product.

Melting point: 115-118 ° C.

Stage B. [4- (Piperidin-1-ylcarbonyl) phenyl] boric acid.

The procedure is the same as in stage B of example 1, but start with the compound obtained in stage

A.

Melting point: 135-140 ° C.

Step C. 1-Cyclopentyl-4- {5- [4- (piperidin-1-ylcarbonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride.

The procedure is the same as in stage C of example 1, but start with the compound obtained in stage

B, and the compound obtained in obtaining 2.

Melting point: 227-230 ° C.

Elemental microanalysis:

FROM N N FROM! % theory 63.54 7.38 11.40 14.43 % experiment 63.45 7.42 11.31 14.46

Example 17. 1-Isopropyl-4- {5- [4- (piperidin-1-ylcarbonyl) phenyl] pyridin-2-yl} piperazine dihydrochloride.

The procedure is the same as in step C of Example 16, but the product obtained in Preparation 2 is replaced with the compound obtained in Preparation 1.

Melting point: 240-243 ° C.

Elemental microanalysis:

C%, theory 61.93 7.36%, experiment 62.14 7.35

C1

12.04 15.23

11.62 15.33

Example 18. 1-Methyl-4- {5- [4- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine dihydro chloride.

The product of step B of Example 2 is reacted with the compound obtained in Preparation 6 under the conditions described in Step C of Example 1.

Melting point: 250-255 ° C.

Elemental microanalysis:

C%, theory 53.27 6.39%, experiment 53.51 6.40

FROM!

11.83 6.77 14.98

11.82 6.71 15.16

Example 19. Y-Cyclopropyl-4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] benzenesulfonamide dihydrochloride.

Stage A. Y-Cyclopropyl-4-iodobenzenesulfonamide.

The procedure is the same as in stage A of example 1, but morpholine is replaced with cyclopropylamine. Stage B. P-cyclopropyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzenesulfonamide The procedure is the same as in stage B of example 9, but start with the product obtained in stage A. Melting point: 99 ° C.

Step C. Y-Cyclopropyl-4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] benzenesulfonamide di hydrochloride.

Example 20. Y- (tert-Butyl) -4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] benzenesulfonamide di hydrochloride.

The procedure is the same as in step C of example 1, but begins with the compound obtained in step B.

Melting point: 269 ° C.

Elemental microanalysis:

FROM N N 8 C1 % theory 53.27 6.39 11.83 6.77 14.98 % experiment 53.22 6.44 11.66 6.51 14.98

Stage A. YY- (tert-Butyl) -4-iodobenzenesulfonamide.

The procedure is the same as in stage A of example 1, but the morpholine is replaced with tert-butylamine.

Melting point: 121 ° C.

Stage B. Y- (tert-Butyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzenesulfonamide. The procedure is the same as in stage B of example 9, but start with the product obtained in stage A.

Step C. Y- (tert-Butyl) -4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] benzenesulfonamide di hydrochloride.

- 10 011155

The procedure is the same as in step C of example 1, but begins with the compound obtained in step B.

Melting point: 215-230 ° C.

Elemental microanalysis:

FROM N N 8 FROM! % theory 53.98 7.00 11.45 6.55 14.48 % experiment 54.19 7.05 11.16 5.25 14.52

Example 21. 4 - ({4- [6- (4-Isobutylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) morpholine dihydrochloride.

The product obtained in stage B of example 1, is reacted with the compound obtained in obtaining 7, under the conditions described in stage C of example 1.

Melting point: 137 ° C.

Elemental microanalysis:

C H%, theory 53.76 6.65%, experiment 54.14 6.57

N 8 C1 10.90 6.24 13.11 10.74 6.06 13.04

Example 22.1-Isopropyl-4 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) piperazine trihydrochloride.

Stage A. 1 - [(4-Iodophenyl) sulfonyl] -4-isopropylpiperazine.

The procedure is the same as in step A of example 1, but the morpholine is replaced with 1-isopropylpiperazine. Melting point: 139 ° C.

Step B. 1-Isopropyl-4 - {[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] sulfonyl} piperazine.

The procedure is the same as in step B of example 9, but begins with the product obtained in step A. Step C. 1-Isopropyl-4 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3 -yl] phenyl} sulfonyl) piperazine trihydrochloride.

The procedure is the same as in stage C of example 1, but start with the product obtained in stage B.

Melting point: 290 ° C.

Elemental microanalysis:

C H%, theory 51.68 6.94%, experiment 51.35 7.39

N 8 C1 12.05 5.52 18.3 11.77 5.35 18.5

Example 23. 4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] benzenesulfonamide dihydrochloride. Stage A. 4-Iodobenzenesulfonamide.

The procedure is the same as in stage A of example 1, but the morpholine is replaced with gaseous ammonia. Melting point: 173 ° C.

Stage B. 4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) benzene-sulfonamide.

The procedure is the same as in Step B of Example 9, but begins with the product obtained in Step A. Step C. 4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] benzenesulfonamide dihydrochloride.

The procedure is the same as in stage C of example 1, but start with the product obtained in stage B. Melting point: 297-301 ° C.

Elemental microanalysis:

FROM N N 8 C1 % theory 49.88 6.05 12.93 7.4 16.36 % experiment 50.05 6.21 12.58 7.39 16.46

Example 24. 4 - ({4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) thiomorpholine 1,1-dioxide dihydrochloride.

To a suspension of 400 mg of the product obtained in example 10 (0.76 mmol), in a mixture of 3 ml of acetone and 12 ml of water, 266 mg of 4-methylmorpholine Ν-oxide (2.27 mmol) and 34 μl of a 2.5% osmium solution are added tetroxide in tert-butanol. After stirring for 16 hours at room temperature, the reaction mixture was treated with saturated sodium bisulfate solution and 10% sodium hydrogen carbonate solution. The mixture was extracted with CH ₂ Cl ₂ , and the organic phases were dried over MgSO ₄ and evaporated under reduced pressure.

The precipitate is treated with methanol HC1 to obtain, after filtration, the title product in the form of a white solid.

Melting point: 278-280 ° C.

- 11 011155

Elemental microanalysis:

FROM

C1%, theory%, experiment Example 25.

5.85

5.68

10.16

10.08

12.86

13.58

47.91

48.57

Ethyl-4 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) piperazine trihydrochloride.

Stage A. 1 - [(4-Iodophenyl) sulfonyl] -4-ethylpiperazine.

The procedure is the same as in stage A of example 1, but the morpholine is replaced with 1-ethylpiperazine. Melting point: 148 ° C.

Elemental microanalysis:

C H%, theory 37.90 4.51%, experiment 37.74 4.50

At 5 one 7.37 8.43 33.37 7.16 8.22 31.85

Step B. 1-Ethyl-4- {[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] sulfonyl} piperazine. The procedure is the same as in stage B of example 9, but start with the product obtained in stage A.

Step C. 1-Ethyl-4 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) piperazine trihydrochloride.

The procedure is the same as in stage C of example 1, but start with the product obtained in stage B. Melting point: 249 ° C.

Elemental microanalysis:

FROM N N 8 C1 % theory 50.84 6.75 12.35 5.66 18.76 % experiment 50.33 6.53 11.84 5.26 18.76

Example 26. 4 - ({4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) thiomorpholine 1 oxide dihydrochloride.

To a solution of 183 ml of NaO ₄ (0.86 mmol) in 8 ml of water was added 424 mg of the product of Example 10, and the reaction mixture was stirred for 1 h at room temperature. The mixture was extracted with CH ₂ Cl ₂ , and the organic phases were dried over MgSO ₄ . After evaporation under reduced pressure, the residue is treated with methanol HC1 to obtain, after filtration, the title product in the form of a white solid.

Melting point: 265 ° C.

Elemental microanalysis:

C H%, theory 49.68 6.04%, experiment 49.91 6.14

N 8 C1 10.53 12.06 12.66 10.03 11.95 12.39

Example 27. 1- {5- [4- (Aziridin-1-ylsulfonyl) phenyl] pyridin-2-yl} -4-isopropylpiperazine dihydrochloride.

Stage A. 1-Cyclopropyl-4 - [(4-iodophenyl) sulfonyl] piperazine.

The procedure is the same as in stage A of example 1, but the morpholine is replaced with 1-cyclo-propylpiperazine.

Melting point: 169 ° C.

Stage B. 1-Cyclopropyl-4 - {[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] sulfonyl} piperazine.

The procedure is the same as in step B of example 9, but begins with the product obtained in step A. Step C. 1-Isopropyl-4 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3 -yl] phenyl} sulfonyl) piperazine trihydrochloride.

The procedure is the same as in stage C of example 1, but start with the product obtained in stage B.

Melting point: 149 ° C.

Elemental microanalysis:

FROM N N 8 C1 % theory 55.34 6.87 12.91 5.91 07/13 % experiment 55.22 7.01 12.52 5.99 12.98

Example 28. 1-Isopropyl-4- (5- {4 - [(2-methylpyrrolidin-1-yl) sulfonyl] phenyl} pyridin-2yl) piperazine dihydrochloride.

Stage A. 1 - [(4-Iodophenyl) sulfonyl] -2-methylpyrrolidine.

The procedure is the same as in stage A of example 1, but the morpholine is replaced with 2-methylpyrrolidine. Melting point: 76 ° C.

Stage B. {4 - [(2-Methylpyrrolidin-1-yl) sulfonyl] phenyl} boric acid.

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The procedure is the same as in stage B of example 1, but start with the product obtained in stage A. Melting point: 125-128 ° C.

Step C. 1-Isopropyl-4- (5- {4 - [(2-methylpyrrolidin-1-yl) sulfonyl] phenyl} pyridin-2-yl) piperazine dihydrochloride.

The procedure is the same as in stage C of example 1, but start with the product obtained in stage A. Melting point: 208-213 ° C.

Elemental microanalysis:

FROM N N 8 C1 % theory 55.08 6.83 11.17 6.39 14.14 % experiment 55.27 6.77 10.95 6.27 14.47

Example 29. 1-Isopropyl-4- {5- [4- (piperazin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine trihydrochloride.

Stage A. tert-Butyl 4 - [(4-iodophenyl) sulfonyl] piperazine-1-carboxylate.

The procedure is the same as in Step A of Example 1, but the morpholine is replaced with tert-butyl piperazine 1-carboxylate.

Stage B. (4 - {[4- (tert-Butoxycarbonyl) piperazin-1-yl] sulfonyl} phenyl) boric acid.

The procedure is the same as in stage B of example 1, but start with the product obtained in stage A.

Step C. tert-Butyl 4 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) piperazine-1-carboxylate.

The procedure is the same as in stage C of example 1, but start with the product obtained in stage A. Melting point: 194 ° C.

Stage Ό. 1-Isopropyl-4- {5- [4- (piperazin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine trihydrochloride.

Deprotection is performed in 1/1 of a mixture of dioxane and methanol HC1.

Melting point: 265-273 ° C.

Elemental microanalysis:

FROM N N 5 C1 % theory 49.03 6.36 12,99 5.95 19.73 % experiment 49.63 6.49 12.86 6.2 20.39

Example 30. 1-Cyclohexyl-4 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) piperazine dihydrochloride.

Stage A. 1-Cyclohexyl-4 - [(4-iodophenyl) sulfonyl] piperazine.

The procedure is the same as in step A of example 1, but the morpholine is replaced with 1-cyclohexylpiperazine.

Melting point: 174-177 ° C.

Elemental microanalysis:

FROM Ή % theory 44.25 5.34 % experiment 44.16 5.33

N 8 I 6.45 7.38 29.22 6.37 7.00 29.07

Step B. 1-Cyclohexyl-4 - {[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] sulfonyl} piperazine.

The procedure is the same as in step B of example 9, but begins with the product obtained in step A. Step C. 1-Cyclohexyl-4 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3 -yl] phenyl} sulfonyl) piperazine dihydrochloride.

The procedure is the same as in stage C of example 1, but start with the product obtained in stage B. Melting point: 276-281 ° C.

Elemental microanalysis:

FROM N N 8 FROM! % theory 57.52 7.41 11.98 5.48 12,13 % experiment 58.01 7.32 12.18 5.2 12.86

Example 31. 1 - ({4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) piperidin-4-one dihydrochloride.

Stage A. 8 - [(4-Iodophenyl) sulfonyl] -1,4-dioxa-8-azaspiro [4.5] decan.

The procedure is the same as in stage A of example 1, but the morpholine is replaced by 1,4-dioxa-8azaspiro [4.5] decan.

Melting point: 166-169 ° C.

Stage B. [4- (1,4-dioxa-8-azaspiro [4.5] dec-8-ylsulfonyl) phenyl] boric acid.

The procedure is the same as in stage B of example 1, but start with the product obtained in stage A. Melting point: 146-148 ° C.

- 13 011155

Step C. 8 - ({4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) -1,4-dioxa-8azaspiro [4.5] decane.

Stage Ό. 1 - ({4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) piperidin-4-one dihydrochloride.

The procedure is the same as in stage C of example 1, but start with the product obtained in stage B. Melting point: 215 ° C.

Elemental microanalysis:

FROM N N 8 %> theory 61.70 7.04 11.51 6.59 % experiment 61.28 7.05 11.54 6.58

A suspension of 400 mg of the product obtained in stage C (0.82 mmol) in 5 ml of 1Ν HCl was stirred for 1 h at 80 ° C. After neutralizing the reaction mixture using 10% NaHCΟ ₃ , the precipitate was filtered off, washed with water and dried. The white solid was suspended in ethanol and dissolved by the addition of methanol HCl. The solution was evaporated to dryness and the residue was taken up in ethanol / ethyl ether to give the expected product after filtration.

Melting point:> 260 ° C.

Elemental microanalysis:

FROM N N 8 C1 % theory 53.59 6.26 10.87 6.22 13.75 % experiment 54.25 6.25 10.84 6.51 13.48

Example 32. 1-Isopropyl-4- (5- {4 - [(2-methylpyrrolidin-1-yl) sulfonyl] phenyl} pyridin-2-yl) piperazine dihydrochloride, enantiomer 1.

the enantiomers of the compounds described in example 28 (free base form) were separated by chiral chromatography on a Syga1rak AO column using a methanol / acetonitrile / diethylamine 150/850/1 mixture as eluent. Hydrochlorides are obtained by treatment with methanol HC1.

Enantiomer 1:

Melting point: 243-247 ° C.

Elemental microanalysis:

С Η N 8С1%, theory 55.08 6.83 11.17 6.3914.14%, experiment 55.31 6.84 10.96 6.3714.58

Example 33. 1-Isopropyl-4- (5- {4 - [(2-methylpyrrolidin-1-yl) sulfonyl] phenyl} pyridin-2yl) piperazine dihydrochloride, enantiomer 2.

the enantiomers of the compounds described in example 28 (in the form of a free base) were separated by chiral chromatography on a Syga1rak AO column using a methanol / acetonitrile / diethylamine 150/850/1 mixture as an eluent. Hydrochlorides are obtained by treatment with methanol HC1.

Enantiomer 2:

Melting point: 245-249 ° C.

Elemental microanalysis:

C Η N 8C!

%, theory 55.08 6.83 11.17 6.3914.14%, experiment 55.41 6.75 11.12 6.3214.85

Example 34. 2 - ({4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptane.

Stage A. 2 - [(4-Iodophenyl) sulfonyl] -5-methyl-2,5-diazabicyclo [2.2.1] heptane.

The procedure is the same as in stage A of example 1, but the morpholine is replaced with 2-methyl-2,5-diazabicyclo [2.2.1] heptane.

Melting point: 149-152 ° C.

Stage B. 2-Methyl-5- {[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] sulfonyl} -2,5 diazabicyclo [2.2.1] heptane .

The procedure is the same as in stage B of example 9, but start with the product obtained in stage A.

Step C. 2 - ({4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptane.

The procedure is the same as in stage C of example 1, but start with the product obtained in stage B.

Melting point: 194-198 ° C.

- 14 011155

Elemental microanalysis:

FROM N N 8 % theory 63.27 7.30 15.37 7.04 %> experiment 63.09 7.36 14.73 6.76

Example 35. 1 - ({4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) -Y, M-dimethylpiperidin-4-amine trihydrochloride.

To a suspension of 242 mg of the product obtained in Example 32 (0.54 mmol), 89 mg of dimethylamine hydrochloride (1.09 mmol), 153 μl Εΐ ₃ Ν (1.09 mmol) and 323 μl of titanium (IV) are added to 2 ml of ethanol. ) isopropoxide (1.08 mmol). After stirring for 16 hours at room temperature, 52 mg Ν; · ιί.'ΝΒΗ. · Ι (0.82 mmol) was added and stirring was continued for 5 hours at room temperature. The reaction mixture was treated with 28% ammonium hydroxide solution and the mixture was extracted with CH ₂ Cl ₂ . The organic phases are dried over MgSO ₄ and, after evaporation under reduced pressure, the precipitate is purified by chromatography on a silica column, eluting with 96/4 CH ₂ Cl ₂ / MeOH. The trihydrochloride is obtained by treating the base with methanol HC1 to obtain, after filtration, the title product in the form of a white solid.

Melting point: 283-286 ° C.

Elemental microanalysis:

from N N 8 FROM! % theory 51.68 6.94 12.05 5.52 18.30 % experiment 51.81 7.08 12.08 4.81 17.86

Example 36. 1-Cyclopentyl-4- (5- {4 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} pyridin-2-yl) piperazine trihydrochloride.

Step A. Tert-Butyl 4 - ({4- [6- (4-cyclopentylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) piperazine-1-carboxylate.

The product obtained in stage B of example 29 is reacted with the compound obtained in obtaining 2 under the conditions described in stage C of example 1.

Melting point: 235-238 ° C.

Elemental microanalysis:

FROM N N 8 % theory 62.68 7.44 12.60 5.77 % experiment 62.56 7.46 12.36 5.89

Step B. 1-Cyclopentyl-4- {5- [4- (piperazin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine.

Deprotection is performed in 1/1 of a mixture of dioxane and methanol HC1. The base is formed again by treatment with 10% No. HN.'O ₃ .

Step C. 1-Cyclopentyl-4- (5- {4 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} pyridin-2-yl) piperazine trihydrochloride.

A suspension of 500 mg of the product obtained in stage B (1.10 mmol), 270 mg of sodium acetate (3.29 mmol) and 66 mg of paraformaldehyde (2.19 mmol) in 10 ml of ethanol was stirred overnight at room temperature. Then, 138 mg of NaCNΒH3 (2.19 mmol) was added in several parts to the reaction mixture and stirring was continued for 6 hours at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was taken up in 1Ν HCl and the mixture was stirred for 30 minutes at room temperature. Then the mixture is alkalinized by adding 1Ν No. 1OH and the white precipitate that forms is filtered off. The precipitate was resuspended in warm ethanol and after adding ethereal HC1 a solution was obtained which crystallized the title product at room temperature.

Melting point: 263-267 ° C.

Elemental microanalysis:

FROM N N 8 C1 % theory 51.86 6.61 12.09 5.54 18.37 % experiment 52.25 6.68 11.96 5.33 18.94

Example 37. 1 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) piperidin-4-ol dihydrochloride.

To a suspension of 1 g of the product obtained in Example 32 (2.26 mmol) in 20 ml of methanol, 257 mg No. 1BH _{3 was} added in several parts. and the reaction mixture was stirred for 2 hours at room temperature. After adding 40 ml of water, the reaction mixture was extracted with CH ₂ Cl ₂ , and the organic phases were combined, dried over MgSO ₄ and evaporated under reduced pressure. The precipitate was resuspended in ethanol and filtered. The solid was dissolved in methanol HCl, the solution was evaporated to dryness and the residue was triturated with ethyl ether to give the title product after filtration.

- 15 011155

Melting point: 162 ° C.

Elemental microanalysis:

FROM N TO 8 C1 % theory 53.38 6.62 10.83 6.2 13.7 % experiment 53.64 6.79 10.88 6.03 12.63

Example 38. 1-Isopropyl-4- (5- {3 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} pyridin-2-yl) piperazine trihydrochloride

Stage A. tert-Butyl 4 - [(3-bromophenyl) sulfonyl] piperazine-1-carboxylate.

The procedure is the same as in Step A of Example 1, but the morpholine is replaced with tert-butyl piperazine 1-carboxylate and 4-iodobenzenesulfonyl chloride with 3-bromobenzene sulfonyl chloride.

Stage B. (3 - {[4- (tert-Butoxycarbonyl) piperazin-1-yl] sulfonyl} phenyl) boric acid. The procedure is the same as in stage B of example 1, but start with the product obtained in stage A. Melting point: 225 ° C.

Step C. tert-Butyl 4 - ({3- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) piperazine-1-carboxylate.

The procedure is the same as in stage C of example 1, but start with the product obtained in stage B. Stage Ό. 1-Isopropyl-4- {5- [3 - (piperazin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine. The procedure is the same as in step B of example 37, but begins with the product obtained in step C. Step E. 1-Isopropyl-4- (5- {3 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl } pyridin-2-yl) piperazine trihydrochloride.

The procedure is the same as in step C of example 37, but begins with the product obtained in step Ό. Melting point: 168 ° C.

Elemental microanalysis:

C H%, theory 49.96 6.56%, experiment 50.07 6.14

N

12.66

12.55

5.8

5.67

C1

19.23

19.47

Example 39

- (5- {4 - [(4-Fluoropiperidin-1-yl) sulfonyl] phenyl} pyridin-2-yl) -4-isopropyl piperazine dihydrochloride.

Stage A. 4-Fluoro-1 - [(4-iodophenyl) sulfonyl] piperidine.

The procedure is the same as in stage A of example 1, but the morpholine is replaced with 4-fluoro-piperidine. Melting point: 130-133 ° C.

Stage B. {4 - [(4-Fluoropiperidin-1-yl) sulfonyl] phenyl} boric acid.

The procedure is the same as in step B of example 1, but begins with the product obtained in step A. Step C. 1 - (5- {4 - [(4-Fluoropiperidin-1-yl) sulfonyl] phenyl} pyridin-2 -yl) -4-isopropylpiperazine dihydrochloride.

The procedure is the same as in stage C of example 1, but start with the product obtained in stage B. Melting point: 243-247 ° C.

Elemental microanalysis:

FROM N N 8 C1 % theory 53.18 6.4 10.78 6.17 13.65 % experiment 52.91 6.4 10.6 5.79 13.46

Example 40. 4- {4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] benzoyl} morpholine dihydrochloride. Stage A. 4- (4-Iodobenzoyl) morpholine.

The procedure is the same as in stage A of example 16, but piperidine is replaced with morpholine.

Stage B. [4- (Morpholin-4-ylcarbonyl) phenyl] boric acid.

The procedure is the same as in stage B of example 1, but start with the compound obtained in stage A. Melting point: 116 ° C.

Step C. 4- {4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] benzoyl} morpholine dihydrochloride. The procedure is the same as in step C of example 1, but begins with the compound obtained in step B. Melting point: 224 ° C.

Elemental microanalysis:

FROM N N C1 % theory 59.1 6.9 11.99 15.17 % experiment 58.68 6.91 11.6 15.05

Example 41. 1-Isopropyl-4- (5- {4 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} pyridin-2-yl) piperazine trihydrochloride.

Stage A. 1- (4-Iodobenzoyl) -4-methylpiperazine.

The procedure is the same as in step A of example 16, but piperidine is replaced with 1-methylpiperazine.

Step B. 1-Methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] piperazine.

- 16 011155

The procedure is the same as in stage B of example 9, but start with the product obtained in stage A. Melting point: 92 ° C.

Step C. 1-Isopropyl-4- (5- {4 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} pyridin-2-yl) piperazine trihydrochloride.

The procedure is the same as in step C of example 1, but begins with the compound obtained in step B. Melting point: 288 ° C.

Elemental microanalysis:

FROM N N but % theory 55.76 7.02 13.55 20.57 % experiment 55.40 7.02 13.08 20,13

Example 42. 1 - ({4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) -Y-methylpiperidin-4-amine trihydrochloride.

The procedure is the same as in example 35, but dimethylamine hydrochloride is replaced with 2M methylamine in methanol.

Melting point: 284-288 ° C.

Elemental microanalysis:

FROM N At 8 C1 % theory 50.84 6.75 12.35 5.66 18.76 % experiment 50.87 6.81 12,13 5.23 18.91

Example 43. (18,48) -5 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) -2-oxa5-azabicyclo [2.2.1] heptane dihydrochloride .

Stage A. (18.48) -5 - [(4-iodophenyl) sulfonyl] -2-oxa-5-azabicyclo [2.2.1] heptane.

The procedure is the same as in stage A of example 1, but the morpholine is replaced by (18.48) -2-oxa-5azabicyclo [2.2.1] heptane.

Melting point: 146-148 ° C.

Stage B. {4 - [(18,48) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylsulfonyl] phenyl} boric acid.

The procedure is the same as in stage B of example 1, but start with the product obtained in stage A.

Step C. 1 - (5- {4 - [(4-Fluoropiperidin-1-yl) sulfonyl] phenyl} pyridin-2-yl) -4-isopropylpiperazine dihydrochloride.

The procedure is the same as in step C of example 1, but begins with the compound obtained in step B.

Melting point: 238-242 ° C.

Elemental microanalysis:

FROM N N 8 FROM! % theory 53.59 6.26 10.87 6.22 13.75 % experiment 53.36 6.34 10.62 5.86 13.80

Example 44. 1 - ({4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) piperidin-4 amine trihydrochloride.

The procedure is the same as in example 35, but dimethylamine hydrochloride is replaced by ΝΗ ₃ .

Melting point: 293-294 ° C.

Elemental microanalysis:

FROM N N 8 FROM! % theory 49.96 6.56 12.66 5.80 19.23 % experiment 49.68 6.84 12.34 5.76 19.18

Pharmacological study of the compounds of the invention.

Example A. Levels Ν ’'- methylhistamine in the brain ΝΜΚ1 of the mouse.

The purpose of this study, which was carried out in accordance with the method of Tau1og and others (Busyet. Rnag .. 1992, 44, 1261-1267), is to evaluate the ex νίνο activity of the compounds of the present invention as antagonists of central histamine receptors of type H3. This activity is detected by measuring, after treatment, intraperitoneally with the help of test compounds, the levels of No. ^1- methylhistamine in the brain, which is the main metabolite of histamine. An increase in brain concentrations of No. ^1- methylhistamine in the brain indicates an increase in histamine turnover by blocking central histamine receptors of type H3.

ΝΜΚ1 mice (18-20 g) are treated intraperitoneally or orally with the compounds of the present invention or their vehicle (20 ml / kg). One hour after pharmacological treatment, the animals are sacrificed, and their brain is removed, frozen in liquid nitrogen, weighed and homogenized in 0.1 N HClO ₄ at 4 ° C. Homogenized products are centrifuged (15000 d, 17 min, 4 ° C). The supernatant is isolated and aliquoted. Aliquots are frozen in liquid nitrogen and stored at -80 ° C until analysis.

Determination of levels of β-methylhistamine in the brain is carried out using radioimmunolo

- 17 011155 chemical analysis (K1A), using the appropriate set of reagents. Tissue No. ¹ levels ^of methylhistamine in tissues are expressed in μg / g fresh brain. Comparison of the levels of No. ^1- methylhistamine in the brain between animals treated with the vehicle (control group) and animals treated with the compounds of the present invention is carried out using a one-way analysis of variance, which is accompanied, if necessary, by a complementary analysis (Dunnet test).

The results show that, at doses of 1 to 10 mg / kg orally, the compounds of the present invention are able to increase endogenous concentrations of Ν'-methylhistamine in the brain by 100%.

As an example, the compounds of examples 1, 5 and 9, which are used at doses of 10 mg / kg orally, and the compound of example 21, which is used at a dose of 3 mg / kg orally, increase the endogenous concentrations of Ν'-methylhistamine in the brain by 105, 197, 121, and 168%, respectively. These results indicate that the compounds of the present invention are potent antagonists of central histamine receptors of type H3.

Example B. Electroencephalographic recordings on freely moving rats.

Adult male Uistar rats are implanted with electrodes located above the frontal and parietal cortex for the duration of the analysis. A cortical electroencephalogram (EEC) is recorded for rats placed inside cells in a noise-canceling room. The compounds and vehicle are administered randomly at 10:00 AM on the same days with a minimum interval of 3 days between each use, with each rat serving itself as a control. The absolute activity power of the delta band of the slow wave (1-4 Hz), which prevails during the sleep of the slow wave and disappears during wakefulness and REM sleep, is averaged over 30 min periods following one after another. For 30 minutes, low and high values of the slow wave delta power indicate signs of wakefulness and sleep, respectively. The results show that the compounds of the present invention increase wakefulness (lower the activity of the delta band) for doses that are in the range between 0.3 and 3 mg / kg ip. As an example, the compound of example 1, which is used at a dose of 0.3 mg / kg, significantly reduces the activity of the delta band for 150 minutes, which is a sign of cortical activity and wakefulness. At a dose of 3 mg / kg, a significantly delayed sleep delay is also observed: the first episode of a slow sleep wave occurs after 73 ± 5 min, after applying the compound of example 1, while in the control group, the first episode of a slow sleep wave occurs after 45 ± 5 minutes.

Example C. Pharmaceutical composition.

The formula for 1000 tablets, each containing a dose of 100 mg

4 - ({4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) morpholine di hydrochloride (Example 3) ............... .................................................. 100g

Hydroxypropyl cellulose 2 g

Wheat Starch 10 g

Lactose................................................. .................................................. ................ 100g

Magnesium Stearate Talc ................

Claims (11)

CLAIM 1. The compounds of formula (I) in which X represents a C (O) or 8O ₂ group; Κ ₁ represents a phenyl group or a ΝΚ ₃ Κ ₄ group in which Κ ₃ and Κ ₄ , which may be the same or different, each represents a hydrogen atom or a linear or branched (C1-C ₆ ) alkyl group or (C ₃ -C ₈ ) cycloalkyl group, or K ₃ and K ₄ together with the nitrogen atom bearing them form a 5- or 6-membered ring, in which one of the carbon atoms can be replaced by a nitrogen, oxygen or sulfur atom or 8O or 8O ₂ a group, a ring described in this way is not necessarily bridged by means of a linear or branched Noah (C ₁ -C ₆ ) alkyl group and / or optionally substituted with one or two identical or different groups selected from halogen, linear or branched (C 1 -C ₆ ) alkyl group, (C ₃ -C ₈ ) cycloalkyl group , hydroxy, oxo and amino groups (optionally substituted by one or more linear or branched _(C1-C6) alkyl groups); K ₂ is a linear or branched (C 1 -C ₆ ) alkyl group or (C ₃ - 18 0 11155 C8) cycloalkyl group, their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base. 2. The compounds of formula (I) according to claim 1, in which K ₃ and K ₄ together with the nitrogen atom carrying them form A 5 or 6 membered ring in which one of the carbon atoms can be replaced by a nitrogen, oxygen or sulfur atom or by an 80 or 8O ₂ group as well as their addition salts with a pharmaceutically acceptable acid or base. 3. The compounds of formula (I) according to claim 1, in which Κι represents morpholinyl, thiomorpholinyl, piperidyl, piperazinyl, 4- (alkyl) piperazinyl, pyrrolidinyl, 2- (alkyl) -2,5-diazabicyclo [2.2.1] heptanyl or 2-oxa-5-azabicyclo [2.2.1] heptanyl group, their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base. 4. The compounds of formula (I) according to claim 1, in which X represents an 8O ₂ group, their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base. 5. The compounds of formula (I) according to claim 1, in which Κ ₂ represents an isopropyl group, their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base. 6. The compound of formula (I) according to claim 1, which is 4 - ({4- [6- (4-isopropylpiperazin-1yl) pyridin-3-yl] phenyl} sulfonyl) morpholine dihydrochloride, as well as its addition salts with pharmaceutically acceptable acid or base. 7. The method of obtaining compounds of formula (I) as defined in claim 1, characterized in that the starting material used is a compound of formula (II) in which Zι and X take the values indicated for formula (I); Κ and Κ ', which may be identical or different, each represent a hydrogen atom or a linear or branched _(C1-C6) alkyl group or together form a linear or branched (C1-C6) alkylene chain which is condensed in the presence of a palladium ( O) with the compound of the formula (III) TO, I Na1; - ν \ __ / - ^Ν (III) in which Κ ₂ takes the values indicated for formula (I), and H1 represents a halogen atom, to obtain a compound of formula (I), where the compound of formula (I) is purified, if necessary , in accordance with conventional purification methods, are separated, if appropriate, into its isomers in accordance with conventional separation methods and, if desired, converted into its addition salt with a pharmaceutically acceptable acid or base. 8. A pharmaceutical composition having antagonistic activity of central histamine receptors of the type H ₃ , which comprises as an active ingredient a compound according to any one of claims 1 to 6 in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers. 9. The pharmaceutical composition of claim 8, used in the manufacture of a drug antagonist of central histamine receptors type H3. 10. The pharmaceutical composition of claim 8, which contains at least one active ingredient according to any one of claims 1 to 6 and is intended for use as a medicine for the treatment of cognitive deficits associated with aging of the brain and with neurodegenerative diseases, and treatment of mood disorders, convulsions, hyperactivity syndrome with a lack of attention, obesity, pain and narcoleptic conditions. 11. The pharmaceutical composition of claim 8, which contains at least one active ingredient according to any one of claims 1 to 6 and is intended for use as a medicine for the treatment of cognitive deficiencies associated with Alzheimer's disease, Parkinson's disease, Peak's disease, Korsakov, and frontal or subcortical dementias of vascular or other origin.